Osteoclasts produce large amounts of the cysteine proteinases cathepsins B, L, and K. Bone resorption depends upon the degradation of the extracellular matrix by cathepsins that are excreted into the attachment zone between osteoclasts and the bone surface. Parathyroid hormone and calcitonin, respectively, induce and suppress cathepsin L secretion and activity in bone. Retinoic acid and estrogen stimulate and inhibit, respectively, cathepsin K expression in osteoclasts. Therefore, cathepsins play a major role in bone resorption, and their expression may be regulated by factors known to modulate bone resorption. Osteoporosis is characterized by a progressive loss of total bone mass and bone density. Type I osteoporosis (peri-menopausal) is hormonally dependent, but type II osteoporosis (senile) occurs in both males and females and is aged-related. Since many of the normal and pathological effects of cathepsin relate to their levels of synthesis, the degree of cathepsin expression could be important in the pathogenesis of osteoporosis, which is one of the leading causes of morbidity in this country, resulting in over one million fractures each year and increased mortality for those with hip fractures. We hypothesize that aging modulates the effects that hormones and cytokines exert upon bone resorption via changes in cathepsin expression by osteoclasts. To test this hypothesis, we wish to perform the following experiments: Specific Aim 1. Determine whether agents active in bone physiology regulate the expression of cathepsins in osteoclasts. Specific Aim 2. Determine whether cathepsin expression by osteoclasts changes with age. Specific Aim 3. Determine whether cathepsin expression correlates with the extent of bone resorption. The data obtained from such pilot studies will form the foundation for future investigation of the signal transduction pathways leading to cathepsin gene expression. Ultimately this could permit us to develop therapeutic strategies that will modulate osteoclast-derived cathepsin activity and prevent the destructive events that accompany osteoporosis.